Didanosine

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Abstract
Didanosine, like zidovudine, stavudine and lamivudine, is a nucleoside analogue reverse transcriptase inhibitor (NRTI). In the target cell for HIV, didanosine is converted to its active moiety, dideoxyadenosine-5’-triphosphate (ddATP), which inhibits HIV reverse transcriptase and terminates viral DNA growth. It is now well established that didanosine therapy produces beneficial effects on virological and immunological markers of HIV disease and improves clinical outcome in adults or children with HIV infection. In numerous clinical trials, pronounced and sustained decreases in plasma HIV RNA levels and increases in CD4+ cell counts occurred in previously untreated or antiretroviral therapy-experienced patients treated with didanosine in combination with at least 1 other antiretroviral drug; zidovudine, stavudine, lamivudine, nevirapine, nelfinavir and hydroxyurea (hydroxycarbamide) are among the drugs that have been given in combination with didanosine. Of note, HIV RNA levels decreased to below the limits of detection in some patients receiving triple or dual therapy with didanosine-containing regimens. In double-blind, placebo-controlled trials, triple therapy with didanosine, zidovudine and nevirapine was significantly more effective than dual therapy with various combinations of these agents in improving surrogate disease markers in treatment-naive patients and in delaying disease progression or death in treatment-experienced patients with advanced disease. Improvements in virological and immunological markers were greater with didanosine-containing triple regimens than with dual therapy or monotherapy in comparative trials. Triple therapy with didanosine, stavudine and indinavir showed efficacy similar to that of various other triple therapy regimens in nonblind comparative trials. Comparator regimens included combinations of stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and didanosine, stavudine and nevirapine. Combination therapy with didanosine plus hydroxyurea as dual therapy or with a third agent produced marked and sustained decreases in HIV RNA levels in the plasma and in lymph nodes. Combination therapy with didanosine and zidovudine delays disease progression and prolongs survival in patients with intermediate or advanced HIV infection. In large, randomised, double-blind, clinical trials, dual therapy with didanosine plus zidovudine was significantly more effective than zidovudine monotherapy in preventing disease progression and prolonging survival in previously untreated or antiretroviral therapy-experienced patients with intermediate or advanced HIV infection. Pancreatitis and peripheral neuropathy are serious adverse effects of didanosine. These effects are dose-related and usually reversible after discontinuation of treatment. Nausea, vomiting, diarrhoea and/or abdominal pain have been reported in patients receiving treatment with the drug. Conclusions: Didanosine is an effective and generally well tolerated drug in previously untreated and antiretroviral therapy-experienced patients with HIV infection. Given once or twice daily, it has an important role as a component of triple combination regimens for the treatment of patients with symptomatic or asymptomatic HIV infection. After passive diffusion into the target cell, didanosine is converted to the active moiety, dideoxyadenosine-5′-triphosphate (ddATP). ddATP inhibits viral reverse transcriptase by competing with the natural substrate for HIV, then being incorporated into viral DNA. This results in the prevention of DNA chain elongation and the termination of viral DNA growth. Didanosine shows good activity against HIV-1 in vitro in T lymphocytes, lymphoblastic cell lines, monocytes and human MT-2 cells. The drug is more active in resting T lymphocytes and monocyte/macrophages than in activated cells. Synergistic activity against HIV-1 (including zidovudine-sensitive and -resistant strains) is observed with didanosine in combination with a number of other agents, including zidovudine, stavudine, delavirdine, interferon-α, ribavirin and hydroxyurea (hydroxycarbamide). Primary resistance to didanosine is mediated by a mutation at codon 74 [Leu to Val (L74V)] in the reverse transcriptase gene of HIV-1. This leads to a 5- to 26-fold reduction in viral sensitivity to the drug. The L74V mutation was detected in HIV-1 isolates from 60 to 65% of patients after 1 year of didanosine monotherapy. The development of mutations at codons 65 [Lys to Arg (K65R)] and 184 [Met to Val (M 184V)] in HIV-1 isolates from patients receiving long term didanosine therapy results in secondary resistance to didanosine; these mutations have been observed in HIV-1 isolates from patients receiving long term treatment with the drug. The K65R mutation produced a 3- to 5-fold decrease in the susceptibility of the virus to didanosine and a 20-fold decrease in sensitivity to lamivudine. Multiple mutations, occurring at codons 41, 67, 70, 215 and/or 219, conferring resistance to zidovudine, have been observed in HIV isolates from patients treated with didanosine for up to 2 years. Administration of didanosine as a component of combination regimens reduces the rate and incidence of didanosine-associated mutations in clinical isolates of HIV-1. The L74V mutation was identified in 4% of patients receiving combination therapy with didanosine and zidovudine compared with 60 to 65% of didanosine monotherapy recipients after 1 year of therapy. The emergence of a Glu to Met mutation at codon 151 (Q151M) and 3 or 4 other mutations has been observed in a small proportion of patients receiving NRTI combination therapy (including didanosine and zidovudine). This mutational pattern confers HIV-1 resistance to all of the NRTIs i.e. multinucleoside resistance. Maximum concentrations of didanosine in the plasma (Cmax) ranged from 0.52 to 2.79 mg/L after multiple oral doses (125 to 375mg twice daily) in adults with HIV infection. In children with HIV infection, Cmax values ranged from 0.5 to 4.1 µmol/L after single doses of 20 to 180 mg/m2. Considerable interindividual variation in the bioavailability of didanosine has been reported in adults (21 to 54%) and children (13 to 29%) after multiple or single oral doses of didanosine. The absorption of the drug is reduced when it is administered with food. The mean didanosine area under the plasma concentration-time curve to 24 hours in patients receiving the drug once daily is similar to that in patients receiving the drug on a twice daily basis. The volume of distribution of didanosine is 54L in adults and 9 to 40 L/m2 in children with HIV infection. The drug is partially metabolised to ddATP or uric acid, or enters the purine metabolic pool. The plasma elimination half-life of didanosine is 0.5 to 2.74 hours in adults or children with HIV infection. In adults, total body clearance of didanosine ranged from 20.1 to 22 L/h after single 300mg oral doses of didanosine. Total body clearance of didanosine is significantly reduced in patients with moderate to severe renal impairment, indicating that dosage reduction is required for this patient group. Interactions have been observed between didanosine and ganciclovir, ciprofloxacin, itraconazole and ketoconazole. Other drugs interacting with didanosine include delavirdine and indinavir. A minor interaction between didanosine and ritonavir has been documented, but was not considered to be clinically relevant. Didanosine, administered as a component of combination regimens or as monotherapy, has been evaluated in the treatment of previously untreated and antiretroviral therapy-experienced patients at various stages of HIV infection, including primary infection. Combination therapy with didanosine and at least 1 other NRTI (e.g. stavudine, zidovudine, lamivudine) [plus an NNRTI or a protease inhibitor in some trials] produced marked and sustained reductions in plasma HIV RNA levels and increases in CD4+ cell counts in antiretroviral therapy-naive patients. Beneficial changes in virological and immunological markers were also observed in antiretroviral-experienced patients treated with didanosine plus stavudine. Triple therapy regimens (e.g. didanosine, zidovudine plus nevirapine) produced significantly greater suppression of plasma HIV RNA and more marked increases in CD4+ cell counts than dual regimens (e.g. didanosine plus zidovudine) in HIV-infected patients with asymptomatic or symptomatic disease. Of note, HIV RNA levels decreased to below the limits of detection in some patients receiving triple or dual therapy with didanosine-containing regimens. Triple therapy with didanosine, stavudine and indinavir showed efficacy similar to that of various other triple therapy regimens in nonblind comparative trials published as abstracts. Comparator regimens included combinations of stavudine, lamivudine plus indinavir, zidovudine, lamivudine plus indinavir and didanosine, stavudine plus nevirapine, and didanosine, stavudine plus lamivudine. Combination therapy with didanosine plus hydroxyurea (plus a third agent in some studies) produced beneficial effects on plasma viral load in patients at various stages of HIV disease. In the Delta and AIDS Clinical Trials Group (ACTG) 175 landmark trials, which were randomised, double-blind and placebo-controlled in design, combination therapy with didanosine and zidovudine (and didanosine monotherapy in ACTG 175) was significantly more effective than zidovudine monotherapy in preventing progression to AIDS or death in previously untreated or antiretroviral therapy-experienced patients with intermediate or advanced HIV infection. Didanosine plus zidovudine was also significantly more effective than zidovudine plus zalcitabine in preventing progression to AIDS or death in antiretroviral therapy-naive patients with intermediate to advanced HIV infection and in antiretroviral therapy-naive and -experienced patients with advanced disease in the Community Programs for Clinical Research on AIDS (CPCRA) 007 trial. A triple drug regimen of didanosine, zidovudine and nevirapine was significantly more effective than dual therapy regimens in delaying disease progression and prolonging survival in patients with advanced HIV disease in another double-blind, placebo-controlled trial. Combination therapy with didanosine plus zidovudine was more effective than zidovudine monotherapy in delaying disease progression and death in infants and children with symptomatic HIV infection in the ACTG 152 trial. Patients who received a combination regimen of lamivudine plus zidovudine had a significantly lower risk of disease progression or death and a lower risk of death than recipients of didanosine monotherapy in another trial. Dual and triple therapy with didanosine-containing regimens produced marked improvements in virological and immunological markers of HIV infection in children. Adverse events during didanosine treatment are more common in patients with advanced HIV disease than in those at earlier stages of the illness. The tolerability profile of didanosine administered as a component of combination therapy is similar to that documented with similar dosages of didanosine monotherapy in patients with HIV infection. No unexpected toxicities were observed when didanosine was administered in dual or combination regimens that included zidovudine, lamivudine, stavudine, hydroxyurea, nevirapine or nelfinavir. Pancreatitis and peripheral neuropathy are serious but rare dose-related adverse effects of didanosine. These effects are usually reversible after discontinuation of treatment. Lactic acidosis with hepatic steatosis has been reported as a rare but potentially life-threatening adverse effect of didanosine. Retinal and visual changes have also been reported. Nausea, vomiting, diarrhoea and/or abdominal pain have been reported in patients receiving didanosine combination therapy or monotherapy. Asymptomatic hyperuricaemia, reversible hyperglycaemia and the development of diabetes mellitus have also been documented in patients receiving didanosine treatment. Didanosine is available as chewable/dispersible buffered 25, 50, 100, 150mg tablets and as 200mg tablets (in some countries). Oral didanosine should be administered on an empty stomach ≥30 minutes before or 2 hours after a meal. Recommended dosages of didanosine for adults and adolescents are based on body weight and are as follows: •≥60kg bodyweight: 200mg (tablet/s) or 250mg (citrate/phosphate buffer solution) every 12 hours; alternatively, a dosage of 400mg (2 × 200mg tablets) once daily is approved in some countries • 2 every 12 hours. Dosage recommendations are unavailable for infants aged ≤3 months. The drug has recently gained approval in Europe and the US for once daily administration. A reduction in the dosage of didanosine is required for patients with renal impairment [creatinine clearance 3.6 L/h (<60 ml/min)].